A novel mechanism causing imbalance of mitochondrial fusion and fission in human myopathies
Open accessAbstract
Mitochondrial dynamics play an important role in cellular homeostasis and a variety of human diseases are linked to its dysregulated function. Here, we describe a 15-year-old boy with a novel disease caused by altered mitochondrial dynamics. The patient was the second child of consanguineous Jewish parents. He developed progressive muscle weakness and exercise intolerance at 6 years of age. His muscle biopsy revealed mitochondrial myopathy with numerous ragged red and cytochrome c oxidase (COX) negative fibers and combined respiratory chain complex I and IV deficiency. MtDNA copy number was elevated and no deletions of the mtDNA were detected in muscle DNA. Whole exome sequencing identified a homozygous nonsense mutation (p.Q92*) in the MIEF2 gene encoding the mitochondrial dynamics protein of 49 kDa (MID49). Immunoblotting revealed increased levels of proteins promoting mitochondrial fusion (MFN2, OPA1) and decreased levels of the fission protein DRP1. Fibroblasts of the patient showed elongated mitochondria, and significantly higher frequency of fusion events, mtDNA abundance and aberrant mitochondrial cristae ultrastructure, compared with controls. Thus, our data suggest that mutations in MIEF2 result in imbalanced mitochondrial dynamics and a combined respiratory chain enzyme defect in skeletal muscle, leading to mitochondrial myopathy.
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Loss-of-function mutations in MiD49 cause severe myopathy in humans, with Complex I and Complex IV deficiency in muscle.
“Loss-of-function mutations in MiD49 cause severe myopathy in humans, with Complex I and Complex IV deficiency in muscle [206].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [206]
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DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass
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- Authors
- Bartsakoulia, M., Pyle, A., Troncoso-Chandía, D., Vial-Brizzi, J., Paz-Fiblas, M. V., Duff, J., Griffin, H., Boczonadi, V., Lochmüller, H., Kleinle, S., Chinnery, P. F., Grünert, S., Kirschner, J., Eisner, V., & Horvath, R.
- Affiliations
- Wellcome Centre for Mitochondrial Research (GB)
- Pontificia Universidad Católica de Chile (CL)
- Medical Genetics Center (DE)
- University of Cambridge (GB)
- University of Freiburg (DE)
- Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
- Corresponding author
- Eisner, Verónica
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-01-19
- Volume
- 27
- Issue
- 7
- Pages
- 1186-1195
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC6159537
- OpenAlex
- W2794394392
- Cited by
- 68
- References
- 41
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 6 · 2023: 3 · 2022: 7 · 2021: 20 · 2020: 14 · 2019: 4 · 2018: 5
- FWCI
- 3.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Human Molecular Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Americanae (AECID Library) (submittedVersion, cc-by-nc-nd)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-nd)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Wellcome Trust (109915/Z/15/Z)
- Wellcome Centre for Mitochondrial Research (203105/Z/16/Z)
- Medical Research Council (MR/N025431/1)
- European Research Council (309548)
- Wellcome Trust Pathfinder Scheme (201064/Z/16/Z)
- Newton Fund (MR/N027302/1)
- European Union Seventh Framework Programme (FP7/2007-2013, 305444 RD-Connect and 305121 Neuromics)
- Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z)
- NIHR
- Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2)
- National Institute for Health Research
- Biomedical Research Centre
- Cambridge University Hospitals NHS Foundation Trust
- University of Cambridge
- Centre for Translational Muscle Disease (G0601943)
- FONDECYT (1150677)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- mitochondrial dynamics, mitochondrial fusion, mitochondrial fission, mitochondrial myopathy, nonsense mutation, consanguinity, complex IV deficiency, cytochrome c oxidase deficiency, mitochondrial DNA copy number, Drp1, mitofusin 2, OPA1, exercise intolerance, skeletal muscle
- MeSH terms
- Electron Transport Complex IV, Female, Fibroblasts, Humans, Male, Muscular Diseases, Peptide Elongation Factors, Mutation, Missense, GTP Phosphohydrolases, Mitochondrial Proteins, Electron Transport Complex I, Primary Cell Culture, Mitochondrial Dynamics
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